Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.
Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2300-5. doi: 10.1073/pnas.1206551110. Epub 2013 Jan 16.
Increased understanding of the precise molecular mechanisms involved in cell survival and cell death signaling pathways offers the promise of harnessing these molecules to eliminate cancer cells without damaging normal cells. Tyrosine kinase oncoproteins promote the genesis of leukemias through both increased cell proliferation and inhibition of apoptotic cell death. Although tyrosine kinase inhibitors, such as the BCR-ABL inhibitor imatinib, have demonstrated remarkable efficacy in the clinic, drug-resistant leukemias emerge in some patients because of either the acquisition of point mutations or amplification of the tyrosine kinase, resulting in a poor long-term prognosis. Here, we exploit the molecular mechanisms of caspase activation and tyrosine kinase/adaptor protein signaling to forge a unique approach for selectively killing leukemic cells through the forcible induction of apoptosis. We have engineered caspase variants that can directly be activated in response to BCR-ABL. Because we harness, rather than inhibit, the activity of leukemogenic kinases to kill transformed cells, this approach selectively eliminates leukemic cells regardless of drug-resistant mutations.
深入了解细胞存活和细胞死亡信号通路中涉及的精确分子机制，有望利用这些分子在不损伤正常细胞的情况下消除癌细胞。酪氨酸激酶癌蛋白通过增加细胞增殖和抑制细胞凋亡来促进白血病的发生。尽管酪氨酸激酶抑制剂，如 BCR-ABL 抑制剂伊马替尼，在临床上已显示出显著的疗效，但由于获得点突变或酪氨酸激酶扩增，一些患者会出现耐药性白血病，导致预后不良。在这里，我们利用半胱氨酸天冬氨酸蛋白酶激活和酪氨酸激酶/衔接蛋白信号的分子机制，通过强制诱导细胞凋亡，为选择性杀死白血病细胞开辟了一条独特的途径。我们已经设计了可以直接响应 BCR-ABL 而被激活的半胱氨酸天冬氨酸蛋白酶变体。因为我们利用而不是抑制致癌激酶的活性来杀死转化细胞，所以这种方法可以选择性地消除白血病细胞，而不管耐药性突变如何。
